Impact of Membrane Drug Transporters on Resistance to Small-Molecule Tyrosine Kinase Inhibitors

详细信息    查看全文

• 作者：Claudia Neul¹ ; Elke Schaeffeler¹ ; Alex Sparreboom² ; Stefan Laufer³ ; Matthias Schwab¹ ; ⁴ ; ⁵ ; ^{Matthias.schwab@ikp-stuttgart.de" class="auth_mail" title="E-mail the corresponding author} ; Anne T. Nies¹
• 关键词：SLC transporters ; ABC transporters ; drug resistance ; tyrosine kinase inhibitors ; interindividual variability ; clinical trials ; pharmacogenomics
• 刊名：Trends in Pharmacological Sciences
• 出版年：2016
• 出版时间：November 2016
• 年：2016
• 卷：37
• 期：11
• 页码：904-932
• 全文大小：4339 K

文摘

Small-molecule inhibitors of tyrosine kinases (TKIs) are the mainstay of treatment for many malignancies and represent novel treatment options for other diseases such as idiopathic pulmonary fibrosis. Twenty-five TKIs are currently FDA-approved and >130 are being evaluated in clinical trials. Increasing evidence suggests that drug exposure of TKIs may significantly contribute to drug resistance, independently from somatic variation of TKI target genes. Membrane transport proteins may limit the amount of TKI reaching the target cells. This review highlights current knowledge on the basic and clinical pharmacology of membrane transporters involved in TKI disposition and their contribution to drug efficacy and adverse drug effects. In addition to non-genetic and epigenetic factors, genetic variants, particularly rare ones, in transporter genes are promising novel factors to explain interindividual variability in the response to TKI therapy.